Summary of the Related Art
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., “Chemical Inhibitors of Cyclin-Dependent Kinases,” Progress in Cell Cycle Research, 1995; 1:351-363). Typical enzymes include serine/threonine kinases such as the cyclin-dependent kinases (cdks) cdk1, cdk2, cdk4, cdk5, cdk6, as well as tyrosine kinases involved in cell cycle regulation. Increased activity or temporally abnormal activation or regulation of these kinases has been shown to result in development of human tumors and other proliferative disorders. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated preclinical antitumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur et al., J. Natl. Cancer Inst., 1992; 84:1736-1740; Int. J. Oncol., 1996; 9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-(hydroxyethylamino)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely et al., Eur. J. Biochem., 1994; 224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham et al., Biology of the Cell, 1995; 83:105-120). More recently, the purvalanol class of cdk inhibitors has emerged as more potent derivatives of olomoucine (Gray N. S. et al., Science, 1998; 281:533-538).
Tyrosine kinases are essential for the propagation of growth factor signal transduction leading to cell cycle progression, cellular proliferation, differentiation, and migration. Tyrosine kinases include cell surface growth factor receptor tyrosine kinases such as FGFr and PDGFr, as well as nonreceptor tyrosine kinases, including c-Src and lck. Inhibition of these enzymes has been demonstrated to cause antitumor and antiangiogenesis activity (Hamby et al., Pharmacol. Ther., 1999; 82(2-3):169-193).
Several pyrido[2,3-d]pyrimidines that inhibit cdks and growth factor-mediated kinase enzymes are known (WO 98/33798). U.S. Pat. Nos. 5,733,913 and 5,733,914 describe 6-aryl-pyrido[2,3-d]pyrimidines.
Despite the progress that has been made, the search continues for low molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders, including restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration, and atherosclerosis. The present invention provides such compounds, their pharmaceutical formulations, and their use in treating proliferative disorders.